Dysfunctional large-scale networks linking PTSD and cognitive impairment

Background and purpose: Post-traumatic stress disorder (PTSD) is associated with increased risk of cognitive impairment (CI), but how large-scale network disruption relates to this vulnerability remains unclear. We examined whether PTSD and cognitive status interact to shape brain network organization. Methods: Resting-state fMRI from 178 age-matched male participants (ADNI-DOD and ADNI cohorts) was analyzed within a 2 × 2 factorial design defined by PTSD status and cognitive status. Cognitive status was classified using the Montreal Cognitive Assessment (MoCA), with CI defined by a MoCA score of 18–26 and cognitively normal (CN) status by a MoCA score >26, yielding four groups; PTSD status was established using the Clinician-Administered PTSD Scale (CAPS), requiring a score ≥40 for the PTSD group and ≤30 for non-PTSD (NPTSD) controls. These criteria yielded four groups: PTSD-CI (n = 46), PTSD-CN (n = 14), NPTSD-CI (n = 55), and NPTSD-CN (n = 63). Functional connectivity matrices (32 regions, Harvard–Oxford atlas) underwent graph-theoretical analysis. General linear models tested main effects and the PTSD × cognitive status interaction for global efficiency, eigenvector centrality, clustering coefficient, local efficiency, degree, and betweenness centrality, adjusting for age, education, APOE ε4 status, and depressive symptoms (FDR-corrected). Results: A significant PTSD × cognitive status interaction was observed across all four dorsal attention network (DAN) nodes—bilateral frontal eye fields and intraparietal sulci—for global efficiency, eigenvector centrality, cost, and degree. These effects were driven exclusively by PTSD-CI versus PTSD-CN differences and were absent in non-PTSD groups, reflecting a reversal of the normally right-lateralized DAN organization. Further interaction effects emerged in the right supramarginal gyrus (salience network) and medial visual network. A PTSD main effect reduced language-network hub function (left inferior frontal gyrus, left posterior superior temporal gyrus), and a cognitive-status main effect involved the left supramarginal gyrus. Conclusions: PTSD and cognitive impairment interact, rather than summate, to produce a distinct network signature characterized by DAN lateralization reversal, identifying PTSD-CI as a neurobiologically distinct phenotype and highlighting the DAN, salience, and language networks as targets.